Diabetic patients not only have increased vascular injury that causes higher morbidity of ischemic heart disease (IHD), but also have larger infarct size, severe heart failure, and higher mortality following a comparable degree of initial ischemic insult. Recent clinical and experimental results have demonstrated that adiponectin (APN) is a novel metabolic regulatory, vasculoprotective and cardioprotective molecule whose reduction found in diabetic patients contribute not only to increased morbidity of IHD, but also to increased MI/R injury in these individuals. Substantial evidence exists that AMP activated protein kinase (AMPK) plays an essential role in APN's metabolic and vasculoprotective effects. However, our preliminary experiments demonstrated that APN's cardioprotective effect in the ischemic heart is largely AMPK-independent but critically depends on adiponectin receptor-1/caveolin-3 interaction. The central hypothesis to be tested in this grant application is that novel adiponectin receptor-1/Caveolin-3 interaction mediated, AMPK-independent signaling pathway(s) initiated by specific APN isoform(s) with specific receptor activation may play a critical role in APN's cardioprotective effects against MI/R injury. Three specific aims will be addressed. Specific Aim 1 will utilize knockout mice and siRNA silencing technique to determine whether different forms of APN may preferentially bind to different type of receptors and protect cardiomyocytes against MI/R injury with different involvement of AMPK signaling system. Specific Aim 2 will combine traditional pharmacologic and modern genetic approaches and attempt to identify the intracellular signaling mechanisms by which APN exerts its anti-oxidative, anti-nitrative, and cardioprotective actions in MI/R hearts. Specific Aim 3 will identify novel cardioprotective targets for diabetic individuals with impaired APN-Caveolin signaling. The novel data resulting from the studies proposed in this application are not only scientifically significant because it will help us to understand the biological significance of ANP assembling and disassembling (presence of different isoforms) and how each isoform exerts its cardioprotective effect, but also clinically significant because it may identify optimal interventions for therapeutical needs under different pathologic conditions.